Effects of turmeric (Curcuma longa) supplementation on glucose metabolism in diabetes mellitus and metabolic syndrome: An umbrella review and updated meta-analysis

Aims This study aims to comprehensively review the existing evidence and conduct analysis of updated randomized controlled trials (RCTs) of turmeric (Curcuma longa, CL) and its related bioactive compounds on glycemic and metabolic parameters in patients with type 2 diabetes (T2DM), prediabetes, and metabolic syndrome (MetS) together with a sub-group analysis of different CL preparation forms. Methods An umbrella review (UR) and updated systematic reviews and meta-analyses (SRMAs) were conducted to evaluate the effects of CL compared with a placebo/standard treatment in adult T2DM, prediabetes, and MetS. The MEDLINE, Embase, The Cochrane Central Register of Control Trials, and Scopus databases were searched from inception to September 2022. The primary efficacy outcomes were hemoglobin A1C (HbA1C) and fasting blood glucose (FBG). The corrected covered area (CCA) was used to assess overlap. Mean differences were pooled across individual RCTs using a random-effects model. Subgroup and sensitivity analyses were performed for various CL preparation forms. Results Fourteen SRMAs of 61 individual RCTs were included in the UR. The updated SRMA included 28 studies. The CCA was 11.54%, indicating high overlap across SRMAs. The updated SRMA revealed significant reduction in FBG and HbA1C with CL supplementation, obtaining a mean difference (95% confidence interval [CI]) of –8.129 (–12.175, –4.084) mg/dL and –0.134 (–0.304, –0.037) %, respectively. FBG and HbA1C levels decreased with all CL preparation forms as did other metabolic parameters levels. The results of the sensitivity and subgroup analyses were consistent with those of the main analysis. Conclusion CL supplementation can significantly reduce FBG and HbA1C levels and other metabolic parameters in T2DM and mitigate related conditions, including prediabetes and MetS. Trial registration PROSPERO (CRD42016042131).

Introduction Type 2 diabetes mellitus (T2DM) has rapidly become a leading global health burden among non-communicable diseases (NCD), given its serious complications, including heart disease, cerebrovascular disease, renal failure, limb amputation and blindness [1]. Over 437.9 million people were living with T2DM in 2019, 80% of whom were in low-and middle-income countries (LMICs). The disease accounts for approximately 1.5 million deaths and 66.3 million disability-adjusted life years worldwide [2]. The rise in T2DM cases along with the public health burden has been much more prominent in the developing than in the developed countries, which may be due to limited healthcare resources, less organized and immature health services, lower health literacy, and limited access to advanced treatment options [3,4].
While the management of T2DM requires multiple interventions ranging from lifestyle modification, social policy, health system management, to public education, access to treatment is always the cornerstone of disease control [5][6][7][8]. The accessibility of advanced treatments among LMICs is limited due to the high cost of newer treatments [9]; thus, many LMICs, especially those in tropical regions, have attempted to uncover the pharmacological properties of native plants that have long been used for medicinal purposes [10]. Some plants have been extensively studied for diabetes, Curcuma longa L. (CL), a member of the Zingiberaceae family, has been used as both food and medicine [11][12][13]. Curcumin and its related compounds, such as curcuminoids and essential oils, have been extensively studied for their antidiabetic effects ranging from molecular mechanisms, cellular signaling, in vitro/in vivo studies and randomized, controlled trials (RCTs) [12,14,15]. Several systematic reviews and metaanalyses (SRMAs) of RCTs [15][16][17][18][19][20] have been performed to assess the anti-diabetic effects of curcumin, but the results obtained were conflicting due to different populations, CL preparation forms, duration of use and outcomes.
An umbrella review (UR) can summarize the findings of these SRMAs and evaluate the quality of evidence, as well as assess the robustness of key findings [21]. Therefore, the present UR of SRMAs of RCTs was conducted to comprehensively review the existing evidence on the effects of turmeric preparations and its related bioactive compounds on glycemic and metabolic parameters in T2DM, prediabetes, and MetS. In addition, an updated MA was also performed by including new RCTs to perform a comprehensive analysis of glycemic and metabolic markers, along with a subgroup analysis of different CL preparation forms.

Study design
The protocols for the UR and updated MA have been registered with the PROSPERO registry (CRD42016042131). This study has complied with the recommendations of the Preferred eligible for review if they met the following criteria: (i) SRMAs of RCTs or individual RCTs; (ii) studied in adult patients with T2DM, prediabetes, or MetS; (iii) investigated the effects of CL supplementation in addition to the standard treatment and compared with the placebo or standard treatment; (iv) compared blood glucose parameters (i.e., fasting blood glucose [FPG], glycated hemoglobin A1C [HbA1C]).

Types of interventions
CL supplementation could be administered in any of the following forms: 1) a whole preparation rich in phytochemicals, e.g., dry rhizome or standardized CL powder; 2) an extract preparation containing only portion of the phytochemicals found in CL, e.g., a standardized curcuminoid extract; and 3) a bioavailability-enhanced preparation, a modified CL preparation containing curcumin or curcuminoids (e.g., nanomicelle curcumin, liposome preparations [e.g., phospholipid complex, phytosome, phosphatidylcholine, phosphatidylserine, or phospholipid curcumin]) or any CL preparation with a low dose of piperine (S2 Table in S1 File).

Outcomes of interest
The primary outcomes were the HbA1C and FBG levels measured 4-16 weeks after receiving CL supplementation. Secondary outcomes were lipid profiles: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). The other selected outcomes were also collected including systolic blood pressure (SBP), diastolic blood pressure (DBP), homeostatic model assessment of insulin resistance (HOMA-IR), uric acid and high sensitivity C-reactive protein (hs-CRP).

Data extraction and quality assessment
Relevant data were extracted by two reviewers (N.P. and K.A.) using a standardized extraction form. The extracted data included study/patient characteristics, interventions, outcomes, and other relevant findings. For outcomes, pooled effect sizes of each outcome (i.e., unstandardized mean difference [UMD]; standardized mean difference [SMD]) along with p-values and corresponding 95% confidence intervals (CI) for both postintervention values and the change from baseline were extracted.
The methodological quality of the studies was independently assessed by at least two reviewers (T.P., P.J., or W.R.) using the AMSTAR 2 tool [23] for SRMAs and the Cochrane risk-of-bias tool (RoB 2) [24] for individual RCTs. All extracted data were cross-checked by at least two other reviewers (P.J., W.R., and A.T.) and discrepancies resolved by consensus.

Quality of evidence
The quality of evidence was evaluated by W.R. and P.J. using GRADEpro 1 GDT software online version [25] based on five domains, namely, the risk of bias, inconsistency, indirectness, imprecision, and publication bias. The quality of evidence was graded as high, moderate, low, or very low.

Data synthesis and statistical analysis
For the UR, the overlap of primary studies was assessed across the included SRMAs [26,27] and assessed using Graphical Representation of Overlap for OVErviews (GROOVE) [28].
For the updated MA, the effect sizes (i.e., UMD, SMD) along with 95% CIs of the glucose and metabolism outcomes were estimated and pooled across studies using the DerSimonian and Laird random-effects model [29]. Heterogeneity and publication bias were assessed using the I 2 statistic and Egger's test [30], respectively.
Pre-specified subgroup analyses were performed for the types of patients (diabetes, prediabetes, and MetS), CL preparation forms (whole powder, extract, and bioavailability-enhanced preparation), and baseline characteristics of patients (including mean body mass index [BMI], lipid and lipoprotein profiles, blood pressure, and blood sugar). Additional post-hoc analyses were also performed for the CL preparation forms. For the sensitivity analyses, small-sized trials (<25th percentile) [31] and trials with a high risk of bias were excluded. All analyses were performed by P.J., T.P., and W.R. using STATA 1 version 17.0 (StataCorp, College Station, Texas, USA) along with the self-programmed STATA 1 for meta-analysis described elsewhere [32]. A.T. and S.N. provided technical analysis advice. A p-value � 0.05 was considered statistically significant.

Umbrella review
Identification and selection of SRMAs and individual RCTs. Of 3,507 identified studies, 14 SRMAs [15-20,33-40] containing 61 individual RCTs were eligible in the UR (Fig 1). For the updated MA, individual RCTs were screened from two sources. First, of the 61 RCTs in 14 SRMAs, 41 studies were excluded since most of them were conducted in non-interested patients leaving 20 studies that met the inclusion criteria. Second, of 774 RCTs retrieved from the updated search, only 8 studies met the inclusion criteria. In total 28 RCTs were included in the updated MA (Fig 2).
Degree of overlap in SRMAs. The degree of overlap of individual included RCTs across SRMAs based on the study-citation matrix is shown in S17 Fig in S1 File. The corrected covered area (CCA) score was 11.54% indicating a high degree of overlap. Thirty-one of 91 RCTs were included in multiple SRMAs, indicating limited incremental information in these SRMAs.
CL supplementation also significantly reduced postintervention insulin and DBP levels with UMDs of -0.663 μIU/mL (95% CI: -1.156, -0.171μIU/mL; p = 0.008) and -2.876 mmHg (95%CI: -4.919, -0.833 mmHg; p = 0.006), respectively. In comparing the differences in the mean changes from baseline, significant reductions of 0.444% (95%CI: -0.750, -0.139%; p = 0.004) in HOMA-IR, 0.686 μIU/mL (95%CI: -0.890, -0.481 μIU/mL; p < 0.001) in insulin and -0.589 mg/L (-1.158, -0.021 mg/L; p = 0.042) for hs-CRP were observed. All results for the MA are provided in S8 Table in S1 File. Subgroup analyses. Figs 5 and 6 show forest plots of the subgroup analyses. For the different CL preparation forms, a significant reduction in FBG from baseline was observed for CL extract and bioavailability-enhanced preparations. However, a significant reduction in HbA1C was noted for all CL preparation forms. In addition, a subgroup analysis based on dose showed that the reduction in FBG and HbA1C levels increased with higher doses. Subgroup analysis based on types of patients showed a significant reduction in FBG from baseline in T2DM and MetS, whereas a significant reduction in HbA1C was observed only in T2DM. Furthermore, the findings of the subgroup analysis based on patient baseline characteristics were consistent with those of the main analysis. Details of the subgroup analyses of the primary efficacy outcomes are presented in S9 and S10 Tables in S1 File. The details of the post-hoc analysis of the secondary outcomes stratified by CL preparation forms are provided in S11 Table in S1 File.
Sensitivity analyses and publication bias. Three sensitivity analyses were conducted: 1) analysis using the fixed effects model; 2) exclusion of trials with a high risk of bias; and 3) exclusion of small-sized studies (<25 th percentile). The results of these analyses remained consistent with those of the overall analysis (S12 Table in S1 File). Publication bias was assessed using funnel plots and Egger's test for all outcomes. The funnel plots were symmetrical (S30-S42 Figs in S1 File) corresponding to the results of the Egger's tests, suggesting no publication bias (S13 Table in S1 File), except for postintervention FBG and BMI outcomes.
Quality of evidence. The quality of direct evidence for all primary outcomes was generally rated moderate. The grade was decreased by inconsistency due to a large heterogeneity (large I 2 ). More details on the quality of evidence are provided in S14 Table in S1 File.

Discussion
Our UR that include 14 SRMAs and an updated MA of RCTs indicated significant reductions due to CL supplementation in FBG and HbA1C of about 8 mg/dL and 0.134% to 0.517%, respectively. In addition, CL extract and bioavailability-enhanced preparations could significantly reduce both FBG and HbA1C.
CL has long been used in Eastern medicine for treating various diseases and symptoms and is one of the most studied medicinal plants on earth. The most recent scientific evidence suggests that CL exhibits various cellular actions that can mitigate diabetes [14]. In vitro studies have shown that CL increases insulin expression and secretion by activating the phosphatidylinositol-3-kinase/protein kinase B/glucose transporter 2 (PI3K/Akt/GLUT2) signaling pathway and upregulates insulin mRNA expression [73]. In mouse models, CL attenuated oxidative stress, dose-dependently reducing the apoptosis of pancreatic β-cells [74]. In hepatocytes and adipocytes, CL reduced glucose uptake by inhibiting the translocation of GLUT4 from the cytosol to the plasma membrane via the insulin receptor substance 1/PI3K/Akt signaling pathway [75]. In the gut, CL inhibited the enzymes involved in glucose digestion, i.e., α-amylase and α-glucosidase [76]. CL also stimulated the secretion of glucagon-like peptide-1, and incretins, which are a validated pathway of important classes of anti-diabetic drugs [77]. Notably, CL upregulated peroxisome proliferator-activated receptor-γ (PPAR-γ) expression in liver cells, thereby downregulating p65 nuclear factor kappa B, a protein complex central to the inflammation [78]. CL curcuminoids also inhibited advanced glycation end-products which are the key mediators associated with metabolic complications [76].
Three forms of CL preparation are most commonly used, namely, whole CL, CL extract and bioavailability-enhanced preparations. The different preparation forms may be administered with different types and doses of bioactive compounds [79]. Studies have shown that bioavailability-enhanced preparations, such as curcumin-phosphatidylcholine phytosome complex, curcumin micelles, water-soluble curcumin formulation containing, or colloidal nanoparticle formulation, increased the absorption of curcumin by 6.9-20.0 times compared with whole CL preparation [79]. Therefore, an assessment of the effects of different CL preparations on outcomes is imperative.
Results from both the UR and the updated MA suggest that CL preparations can reduce FBG and modest HbA1C. Interestingly, subgroup analysis showed that CL exhibited beneficial effects on glycemic management, especially in T2DM, pre-diabetes, MetS, and high SBP/DBP. Similar positive effect on glucose homeostasis had also been proved in nonalcoholic fatty liver disease [80]. Regardless of the preparations used, a dose-response relationship was observed, where higher doses of the same preparation elicited stronger effects. In addition, significant reductions in other metabolic parameters were observed, further confirming the potent effects of CL that may be expressed via multiple pathways.

Limitations and strengths
Our study has several limitations. First, the quality of SRMAs were all considered critically low. Second, some relevant outcomes (i.e., HOMA-IR, insulin, blood pressure, CRP) were reported in only a few studies. Hence, the effect sizes were not accurately estimated. Third, differences in bioactive compounds contained in various preparations may exist, which may affect the clinical effects. Such differences are due to varying qualities of the raw materials, extraction methods, and formulation techniques.

Conclusions
Our review revealed that CL supplementation can significantly reduce FBG and HbA1C levels in T2DM and mitigate related conditions, including prediabetes and MetS, after short-term use. The effects appear consistent regardless of the form of CL preparation used. A doseresponse relationship is suggested in the findings, where higher doses of the same preparation elicited stronger responses. In addition, significant reductions in other metabolic parameters were observed. Further studies should be conducted to assess whether the effects on glycemic management can be sustained on a long-term basis and/or whether they can reduce the risk of diabetic complications.